Mammalian exposure to toxic levels of alkyltin compounds (e.g., triethyltin (TET) and trimethyltin (TMT) results in pathological manifestations largely restricted to the nervous system. The outstanding features of TET toxicity are cerebral edema and muscular weakness. Unlike other classical peripheral neuropathies (i.e., acrylamide toxicity), TET intoxication induces minimal, if any, ultrastructural damage to peripheral myelin and nerves. This finding has led to suggestions that the neuromuscular junction may be preferentially affected by TET. In support of this hypothesis, preliminary studies from my laboratory and others indicate that neurotransmission is functionally depressed at the myoneural junction following either acute or chronic exposure to TET. We have shown that the release of acetylcholine is decreased in TET-treated rats. Moreover, Allen and coworkers have demonstrated electrophysiologically that TET in vitro depresses evoked transmitter release, thus confirming the earlier work of Stoner and coworkers and suggesting pre-synaptic involvement. In the proposed work the basic mechanisms of trialkyltin toxicity at the myoneural junction will be sought by a combined neurochemical, electrophysiological and histological approach. A vascularly perfused rat phrenic nerve-diaphragm preparation will be used to study the differential effects of in vitro and in vivo TET and TMT on the release of endogenous acetylcholine under conditions of rest and stimulation. The electrophysiological events of neuromuscular transmission will be investigated using intracellular recording techniques. Nerve conduction velocities of the phrenic and sciatic nerves will be monitored over the time-course of tin intoxication in order to assess possible nerve damage. Nerve, endplate region and muscle will be examined with light and electron microscopy in an attempt to correlate functional changes with ultrastructural abnormalities. In addition, the concentration of metallic tin will be measured in these areas by atomic absorption spectrophotometry. The reversibility of cholinergic deficits will be studied in animals allowed to recover from chronic tin exposure. Thus, this project is designed to cricically evaluate the effects of acute and chronic exposure to trialkyltin compounds on the pre- and post-synaptic events of neuromuscular transmission and to examine the neurobiological alterations during recovery from symptomatic tin exposure.